Evidence-based pharmacological prophylaxis recommendations for venous thromboembolism in hospitalized acutely ill medical patients: a systematic review of clinical practice guidelines

Abstract Venous thromboembolism is a complex multifactorial disease considered the most common cause of preventable deaths in hospitalized patients. Recommendations about pharmacological venous thromboembolism prophylaxis in adult hospitalized patients are available in clinical practice guidelines for optimization of healthcare delivery and improvement of patient outcomes. We conducted a systematic review of clinical practice guidelines using ADAPTE to synthesize recommendations for pharmacological prophylaxis of venous thromboembolism in hospitalized medical patients at a medium complexity university hospital. Recommendations for pharmacological prophylaxis were extracted from seven clinical practice guidelines considered of high quality after assessment with the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. These recommendations will support discussion with specialists and implementation of practices in the setting of the hospital studied.


INTRODUCTION
Venous thromboembolism (VTE), a complex multifactorial disease, is considered the most common cause of preventable deaths in hospitalized patients and thromboprophylaxis is an important strategy to improve patient safety in hospitals. 1 The annual average incidence of thrombotic events in the United States and Europe varies between 1 and 2 per 1000 in the adult population, depending on age, sex, race and medical conditions. 2 The incidence of confirmed hospital-acquired deep vein thrombosis is 10 to 40% in medical and surgical patients in the absence of thromboprophylaxis. 3 Prophylaxis for VTE is wellestablished in worldwide guidelines, but 37% of medical and surgical patients at moderate risk and 29% of those at high risk are not given adequate prophylaxis. 4 Clinical Practice Guidelines (CPGs) are tools that contain recommendations on clinical health interventions based on systematic reviews of evidence and constitute an important element for improving VTE prevention. 5,6 Organizations may choose to adopt recommendations from existing CPGs, develop CPGs with recommendations based on available evidence, or adapt existing recommendations extracted from CPGs, considering local context. 7 Adaptation is an efficient option to avoid duplication of guidelines and ensure implementation of recommendations that consider the local cultural and organizational context. 8 The adaptation process must be rigorous and transparent to produce a high-quality CPG. 9 The ADAPTE Collaboration, an international collaboration of researchers, guideline developers, and guideline implementers, has developed a tool taking a systematic approach to adaptation of high-quality CPGs for health care institutions considering the organizational and cultural environment for application in a different context. Matrices of recommendations and evidence levels must be drawn from the CPGs and grouped together by similarity, helping specialists to identify recommendations with strong evidence and clinical relevance. 10 Several organizations have used the ADAPTE framework for CPG adaptation. 11 Given the epidemiological importance of the disease, and in order to promote safe practices for prophylaxis of venous thromboembolism, we conducted a systematic review of published CPGs to synthesize recommendations for pharmacological VTE prophylaxis of medical patients hospitalized in a medium complexity teaching hospital by similar meaning.

Study design
A systematic review was conducted to identify high-quality CPGs to obtain a synthesis of their recommendations for pharmacological VTE prophylaxis of hospitalized adult medical patients. The study was registered on the protocol registration portal, International Prospective Register of Systematic Reviews (PROSPERO), under number CRD42021232578, and is written following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 12

Clinical question
The first step was formulating the clinical question grounded on the acronym P (population), I (intervention), P (professional), O (outcome), H (health system), as described in Table 1.
Health question: Which drugs have clinical evidence for the prophylaxis of adult medical patients hospitalized in public institutions of medium complexity?

Search strategy
The clinical question guided the search for CPGs through definition of descriptors and inclusion criteria. The inclusion criteria were: CPGs defined by the Institute of Medicine (IOM) 5 open access, in up to date versions in English, Portuguese, or Spanish, published between January 1, 2011 and March 31, 2021.
The following items were outside the scope of this study: pregnant and postpartum women, pediatric patients, outpatients, patients being treated for VTE, and patients suspected of or diagnosed with COVID-19.
An electronic database search was conducted in April 2021 for CPGs on pharmacological prophylaxis in adult hospitalized patients. For all CPGs included in the study, the most up to date version available by December 2022 was sought.
A search strategy was implemented using the keywords "venous thromboembolism" and "guideline" on the following databases: Medical Literature Analysis and Retrieval System Online -Medline (via PubMed), the Cochrane Library (via CENTRAL), Embase, and Latin American & Caribbean Health Sciences Literature (LILACS). Search strings were constructed using specific indexing terms for each of the databases ( Table 2).
A manual search was also conducted on specific CPG repositories and organization websites using the keyword "venous thromboembolism":  Table 2. Search strategies used to obtain clinical practice guidelines with pharmacological prophylaxis for venous thromboembolism from PubMed, Cochrane Library, Embase, and Lilacs.

Selection of clinical practice guidelines
The references retrieved were exported to Rayyan ® reference manager and duplicates were excluded (duplicates not found by the software were deleted manually). Two reviewers (APCS and FCG) independently screened the retrieved titles and abstracts. After the first screening, two reviewers (APCS and FCG) screened the full texts.
Discrepancies found in this process were discussed between the two reviewers and resolved through consensus. When no consensus was reached, a third reviewer participated in the discussion. The same method was used for all subsequent processes until conclusion of extraction of the recommendations.

Data extraction
Two reviewers (APCS and MSS) independently extracted the following data, from each of the included CPGs, using a piloted standard form on Google Forms®, followed by transfer to an Excel® spreadsheet: year of publication, development country, development institution or organization, development method, formal consensus for formulation of the recommendation, financial contributions, funding organizations, classification of evidence, application of GRADE, professionals involved in the development group, perspectives from the patient, patients in the development group, external review, and predicted update schedule.

Quality assessment
The quality assessment was conducted by three reviewers (APCS, FCG & GCHF-M) independently trained in the AGREE II instrument. The training process included an initial discussion of the AGREE II manual, followed by assessment of the quality of CPGs for the treatment of chronic pain 14 and Gaucher's disease 15 on the online platform My AGREE Plus. After these assessments, reviewers and trainer discussed the scores and the discrepancies. Finally, the team evaluated two recent CPGs for obesity and hyperthyroidism 16,17 and engaged in a discussion about the tool and discrepancies.
The AGREE II instrument consists of 23 items grouped in six domains. Each item was given three grades, one from each reviewer, directly on the online platform My AGREE Plus. 18 Each AGREE II item is scored using a 7-point Likert scale, where 1 indicates that there is no information for the AGREE II item and 7 indicates that the information is of the highest possible quality. 10 Grades were considered discrepant when there was a difference of two or more points between different reviewers' grades.
A high-quality CPG was defined using the AGREE II domain scores, with a cut-off of 60% or more for AGREE II domains 3 (rigor of development) and 6 (editorial independence). 19

Synthesis of recommendations
Two reviewers (APCS and MSS) independently read each CPG to acquire an overall impression of their content and procedures and extracted recommendations to an Excel® spreadsheet, using an exact translation of the wording of each recommendation. We compared the different therapeutic strategies and terminologies between CPGs and similar recommendations were synthesized in a table with the level of evidence and the strength of each recommendation.

Ethics and dissemination
No ethical approval is required for this type of systematic review, since no patient data is used. The research results will be presented at conferences and submitted to a peer reviewed journal.

Selection of CPGs
The bibliographic search identified 4,698 records from databases of which 478 were duplicates. The authors screened the 4,220 remaining references by title and abstract and excluded 4,064 that were not in the selection criteria. They then reviewed the full text of 156 documents and excluded 142 documents. Fourteen CPGs were included (Figure 1).

CPG quality assessment
The methodological quality of fourteen (14) CPGs was assessed using the AGREE II instrument and seven guidelines obtained scores greater than or equal to 60% in domains 3 and 6 and were thus defined as of high quality, as follows: 1. National Institute for Health and Care Excellence: Venous thromboembolism in over 16s Reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism (NICE), 31 2. American Society of Hematology guidelines for management of venous thromboembolism: Prevention of venous thromboembolism in surgical and medical hospitalized patients (ASH), 33

Synthesis of recommendations
The synthesis of the recommendations for pharmacological prophylaxis of VTE in acutely ill medical patients is provided in Table 3.

DISCUSSION
In this review, we systematically identified seven (7) high quality CPGs and synthesized a list of recommendations from them, noting the level of evidence and the strength of the recommendations for pharmacological prophylaxis of VTE in acutely ill medical patients.
For pharmacological prophylaxis strategies in acutely ill medical patients, the CPGs recommended low molecular weight heparin (LMWH), 23,24,28,29,31,33 unfractionated heparin (UFH), [22][23][24]28,33 and fondaparinux. 23,28,29,31,33 The LMWH was cited as first choice by NICE 31 because of the clinically beneficial effects and was preferred by the AWMF 29 due to the lower risk of thrombocytopenia. SIGN 28 and ASH 33 suggested LMWH over UFH, with  Recommends inpatient over inpatient plus extended--duration outpatient venous thromboembolism prophylaxis with heparin and direct oral anticoagulants ASH Moderate certainty in the evidence of effects certainty in these estimated effects was low owing to imprecision of the estimates and indirect comparisons) Strong a LMWHs are preferred to UFH because of their longer half-life, lesser tendency to cause heparin associated thrombocytopenia, and once daily dosing schedule (recommended best practice based on the clinical experience of the guideline development group) b Preferably with LMWH in high-risk prophylaxis doses. c LMWH (low certainty in the evidence of effects: certainty in these estimated effects was rated as very low owing to risk of bias and imprecision of the estimates) or fondaparinux (very low certainty in the evidence effects: certainty in these estimated effects was very low owing to the risk of bias, the indirect comparison, and imprecision of the estimates) rather than UFH. d LMWH as first-line treatment and if LMWH is contraindicated use fondaparinux. e The quality of evidence was assessed by outcomes using GRADE. After evaluation, the evidence was interpreted for development of recommendations considering the balance between benefits, harm, and cost of each intervention. Recommendations based on weak, conflicting, or absent evidence were developed based on expert opinion. Strong recommendations were described as "offer" and weak recommendations as "consider". f Until full mobility is restored or until discharge from hospital, whichever comes first. g At least 7 days.
low evidence level, because of its long half-life, its lower likelihood of causing heparin-associated thrombocytopenia, and its once daily dosing schedule. ASH 33 recommended LMWH over direct oral anticoagulants (DOAC) with moderate evidence, due to the increased risk of bleeding using DOAC compared with LMWH. For duration of prophylaxis, three CPGs 23,29,31 recommended from 6 to 14 days and both ACCP 23 and ASH 33 recommended not extending prophylaxis for outpatients. All hospitalized patients should be assessed for risk of VTE and bleeding and pharmacological prophylaxis should be initiated for patients without contraindications. 34 Acutely ill medical patients are exposed to risk factors for developing VTE due their acute medical illness and the prolonged immobility during the illness. 35 Prophylaxis and duration of treatment in medical patients has always been controversial and has been widely discussed. The findings of reviews recommend LMWH, UFH, and Fondaparinux for pharmacological prophylaxis. 35 The Medical Patients with Enoxaparin Trial (MEDENOX) was a prospective, double-blind, randomized, placebo-controlled study conducted from 1996 to 1998 that recruited 1,102 medical patients from 68 centers and 9 countries aged over 40 years and hospitalized for at least 3 days with acute illness who were given low molecular weight heparin (enoxaparin) for 6 -14 days and had a lower incidence of VTE compared with the placebo study group (5.5% vs. 15.0%, p <0.001). 36 The Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT) was an international, multicenter, randomized, double-blind, placebo-controlled study, conducted from July 2001 to April 2002 with the objective of evaluating the efficacy and safety of dalteparin for the prevention of VTE. It randomized 3,706 medical patients hospitalized for at least 4 days for acute illness aged over 40 years to receive dalteparin or placebo for 14 days. The group that received dalteparin had a lower incidence of VTE, 45% (P=0.0015) than the placebo group. 37 A placebo-controlled trial to determine the efficacy of fondaparinux was conducted by the ARTEMIS group from March 2002 to January 2003, recruiting 644 patients aged over 60 with medical illness who received fondaparinux for 14 days and had a lower incidence of VTE (5.6%) than a placebo group (10.5%) (95% CI 7.7% to 69.3%). 38 Prolonged prophylaxis for acutely ill clinical patients has shown equal benefit for reducing VTE, but has also led to an increased risk of bleeding in acutely ill clinical patients.
The Extended Prophylaxis for Venous Thromboembolism in Acutely Ill Medical Patients With Prolonged Immobilization (EXCLAIM) study was a clinical, multicenter, prospective, randomized, double-blind, placebo-controlled trial of extended prophylaxis for thromboembolism in 4,726 patients that aimed to compare the efficacy and safety of extended prophylaxis of VTE with enoxaparin for a longer period of time (28 +/-4 days) to placebo after enoxaparin prophylaxis for 10 +/-4 days in both groups. In the extended enoxaparin prophylaxis group, the incidence of VTE was lower compared to the placebo group (2.5% vs. 4%; with an absolute risk difference favoring enoxaparin -1.53% [95.8%CI, -2.54% to -0.52%]) but the number of bleeding events was higher (0.8% vs. 0.3%; with an absolute risk difference favoring placebo, 0.51% [95%CI, .12% to 0.89%]). 39 A double-blind, double-dummy, placebo-controlled study (ADOPT) conducted from 2007 to 2011 recruited 4,495 acutely ill clinical patients to receive either apixaban for 30 days or enoxaparin for 6 to 14 days resulted in 2.71% VTE-related deaths among patients receiving extended prophylaxis with apixaban (60/2.211) compared to 3.06% among patients receiving short-term prophylaxis with enoxaparin (70/2.284) (relative risk with apixaban, 0.87; 95%CI, 0.62 to 1.23; P=0.44). Bleeding events occurred in 0.47% of the apixaban extended prophylaxis group (15/3.184) and in 0.19% of patients receiving enoxaparin (relative risk with apixaban, 2.58; 95%CI, 1.02 to 7.27; P=0.04). 40 Another multicenter, randomized, parallel group study, conducted from 2007 to 2010, compared safety and efficacy of rivaroxaban or enoxaparin for prevention of venous thromboembolism in hospitalized acutely ill medical patients (MAGELLAN) given subcutaneous enoxaparin 40 mg once a day for 10±4 days and oral placebo for 35±4 days or subcutaneous placebo for 10±4 days and oral rivaroxaban 10 mg once a day for 35±4 days. It was concluded that rivaroxaban was non-inferior to enoxaparin for standard duration thromboprophylaxis and in extended use rivaroxaban reduced the risk of venous thromboembolism, but was associated with an increased risk of bleeding. 41 These recommendations should be used by healthcare organizations to develop and implement contextualized information for health professionals through a critical assessment by experts of those synthesized in matrices. Issues such as developer and patient values and costs should also be considered.
The process of synthesizing recommendations for pharmacological prophylaxis of VTE in acutely ill medical patients was conducted in a systematic and transparent manner. Since the recommendations obtained reflect the content of the CPGs, the methodological quality appraisal conducted using AGREE, a tool accepted as a gold standard for guideline evaluation, was an important element. The recommendations were classified according to their evidence levels and recommendation grades. All steps were conducted by at least two reviewers.
However, the evaluation process is subjective and only the grades for 2 AGREE domains were used to define high quality CPGs. The AGREE is a methodological quality assessment tool and the recommendations of clinical practice guidelines that were excluded due to lack of detail in the description of their methods cannot be considered to have no credibility.
CPGs published in languages other than English, Spanish, or Portuguese were excluded. In addition, each CPG described their recommendations according to the local context, which makes it necessary to interpret recommendations to avoid changing their meaning.

CONCLUSION
In conclusion, the present systematic review synthesized recommendations for pharmacological prophylaxis of VTE in acutely ill medical patients from seven high quality CPGs.
The clinical practice guidelines selected used different clinical questions, scoring systems, and consensus processes to indicate levels of evidence, which may explain discrepancies in the strength of their recommendations. They also considered the availability of studies, drugs approved by local regulatory agencies, and the local context, which may explain the differences between their medication preferences.
These evidence-based recommendations provide support for discussions with specialists to implement contextualized information in health professionals' settings.